Compound, composition and uses thereof

ABSTRACT

The disclosure herein provides the compounds of Formulas 1 and its pharmaceutical acceptable salts, as well as polymorphs, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral administration, transdermal administration, and/or injection. Such compositions may be used for the treatment of metabolic conditions, cystinosis, non-alcoholic Steatohepatitis, hypertriglyceridemia, and/or neurodegenerative disorders, and/or their associated complications.

CLAIM OF PRIORITY

This application is a continuation application of U.S. non-provisionalpatent application Ser. No. 13/858,045 titled “COMPOUND, COMPOSITION ANDUSES THEREOF” filed on Apr. 6, 2013. Which is a continuation applicationclaiming priority to co-pending U.S. non-provisional patent applicationSer. No. 13/649,094 titled COMPOUND, COMPOSITION AND USES THEREOF filedon Oct. 10, 2012, which claimed priority to Ser. No. 13/152,864, filedon Jun. 3, 2011, India Provisional Patent Application No. 3947/CHE/2012,filed on Sep. 24, 2012 and is the national phase application of PCTapplication No. PCT/IN/2012/000668 filed on Oct. 9, 2012. Theseapplications are hereby incorporated by reference in all of theirentireties for all of their teachings.

FIELD OF TECHNOLOGY

This disclosure generally relates to compounds and compositions for thetreatment of metabolic conditions, cystinosis, non-alcoholicsteatohepatitis, hypertriglyceridemia and neurodegenerative diseases.More particularly, this invention relates to treating subjects with apharmaceutically acceptable dose of compounds, crystals, esters, amides,salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND

Metabolism is the process the body uses to get or make energy fromproteins, carbohydrates and fats. Cystinosis is a disorder in which thebody accumulates the amino acid cystine (a building block of proteins)within cells. Excess cystine forms crystals that can build up and damagecells. These crystals negatively affect various systems in the body,especially the eyes, spleen, liver, bone marrow and kidneys. Cystinosisis an autosomal recessive disorder, caused by mutations of the lysosomalcystine carrier cystinosin, encoded by the CTNS gene (17p13). Theconcomitant intralysosomal cystine accumulation leads to multi-organdamage, with kidneys being the first affected and later spleen, eyes,liver and bone marrow. Altered mitochondrial oxidative phosphorylationhas been demonstrated in animal proximal tubules loaded with cystinedimethyl ester, mimicking cystine accumulation in cystinosis, but hasnot been confirmed in cells of patients with cystinosis.

Non-alcoholic steatohepatitis (NASH) is a liver disease characterized bymacrovesicular steatosis, hepatocyte necrosis, inflammation, Mallorybodies, and fibrosis. NASH is closely associated with the metabolic orinsulin resistance syndrome. Oxidative stress is believed to play animportant role in pathogenesis of NASH. It is likely involved in theprogression of disease from steatosis to NASH and potentially cirrhosis.It has been shown that chronic oxidative stress, generated through theoxidation of cytotoxic free fatty acids, can lead to upregulation ofcytokines, induction of the liver cytochrome P450 enzyme 2E1, anddepletion of hepatic antioxidant concentration.

Neurodegenerative disorders are a heterogeneous group of diseases of thenervous system, including the brain, spinal cord, and peripheral nervesthat have much different aetiology. Many are hereditary; some aresecondary to toxic or metabolic processes. Free radicals are highlyreactive molecules or chemical species capable of independent existence.Generation of highly Reactive Oxygen Species (ROS) is an integralfeature of normal cellular function like mitochondrial respiratorychain, phagocytosis and arachidonic acid metabolism. The release ofoxygen free radicals has also been reported during the recovery phasesfrom many pathological noxious stimuli to the cerebral tissues. Some ofthe neurodegenerative disorders include Alzheimer's disease,Huntington's disease, Parkinson's disease and Lateral sclerosis.

Hypertriglyceridemia is a commonly encountered lipid abnormalityfrequently associated with other lipid and metabolic derangements. TheNational Cholesterol Education Program recommends obtaining a fastinglipid panel in adults over the age of 20. The discovery ofhypertriglyceridemia should prompt an investigation for secondary causessuch as high fat diet, excessive alcohol intake, certain medications,and medical conditions (eg, diabetes mellitus, hypothyroidism). Inaddition, patients should be evaluated for other components of themetabolic syndrome. These include abdominal obesity, insulin resistance,low high-density lipoprotein (HDL), high triglyceride, and hypertension.Hypertriglyceridemia is classified as primary hypertriglyceridemia whenthere are no secondary causes identified.

Hypertriglyceridemia is a risk factor for pancreatitis and it accountsfor 1 to 4% of cases of acute pancreatitis. Although a few patients candevelop pancreatitis with triglyceride levels>500 mg/dL, the risk forpancreatitis does not become clinically significant until levelsare >1000 mg/dL. More importantly however, hypertriglyceridemia istypically not an isolated abnormality. It is frequently associated withother lipid abnormalities and the metabolic syndrome (abdominal obesity,insulin resistance, low high-density lipoprotein (HDL), hightriglyceride, and hypertension), which are linked to coronary arterydisease.

Managing acute pathology of often relies on the addressing underlyingpathology and symptoms of the disease. There is currently a need in theart for new compositions to treatment of metabolic conditions such ascystinosis, non-alcoholic Steatohepatitis, hypertriglyceridemia andneurodegenerative disorders.

SUMMARY OF INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods of synthesizing and for using the same to treat,prevent and/or ameliorate the effects of the conditions such ascystinosis, NASH, hypertriglyceridemia, metabolic conditions andneurodegenerative diseases.

The invention herein provides composition comprising of formula I andtheir pharmaceutical acceptable salts thereof. The invention alsoprovides pharmaceutical compositions comprising one or more compounds offormula I and their intermediates thereof and one or more ofpharmaceutically acceptable carriers, vehicles or diluents. Thesecompositions may be used in the treatment of metabolic conditions andneurodegenerative disorders and its associated complications.

In certain embodiments, the present invention relates to the compoundsand compositions of formula I, or pharmaceutically acceptable saltsthereof,

Wherein, R¹, R² each independently represents at least one of hydrogen,methyl, amine, cyclohexyl methyl ether, butoxy, propoxy, thiol, alkyl,alkyl thiol, acetyl thiol, acetyl, disulfide, acyl, acylalkyl, alkenyl,alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl,aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, amide,heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, orhydroxyalkyl;

R² also independently represents at least one of hydrogen, carboxyl,amine, —NH—CO—NH—, —NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol, disulfide,

R³ independently represents at least one of

In certain embodiments, the present invention relates to the compoundsand compositions of formula 1 or pharmaceutically acceptable saltsthereof,

In one embodiment, steps of synthesizing the compounds of formula 1 isdescribed.

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of metabolic conditions,non-alcoholic steatohepatitis, neurodegenerative disorder or its relatedcomplications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated forsystemic administration, oral administration, sustained release,parenteral administration, injection, subdermal administration, ortransdermal administration.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from metabolic conditions, non-alcoholic steatohepatitis,neurodegenerative disorders or its related complications manifested frommetabolic conditions, chronic diseases or disorders; Hepatology,Hematological, Orthopedic, Cardiovascular, Renal, Skin, Neurological orOcular complications.

BRIEF DESCRIPTION OF FIGURES

Example embodiments are illustrated by way of example and not limitationin the figures of the accompanying drawings, in which like referencesindicate similar elements and in which:

FIG. 1: Illustrates the synthesis of a compound of Formula 1.

FIG. 2: Illustrates the synthesis of a compound of Formula 2.

FIG. 3: C¹³ NMR results of a compound of Formula 1.

FIG. 4: H¹ NMR results of a compound of Formula 1.

FIG. 5: H¹ NMR results of a compound of Formula 2.

FIG. 6: C¹³ NMR results of a compound of Formula 2.

FIG. 7: Displays comparative study data of oral administration ofKB-ND-002 (Formula 1), Cysteamine or Eicosapentanoiec acid in male mice,concentration versus time profiles were partially evaluable forPharmacokinetic purposes.

DETAILED DESCRIPTION Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C1-C30 for straight chains, C3-C30 for branchedchains), and more preferably 20 or fewer. Likewise, preferredcycloalkyls have from 3-10 carbon atoms in their ring structure, andmore preferably have 5, 6 or 7 carbons in the ring structure.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms. Examples of alkyl groups include, but are not limited to, methyl(Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl (n-Pr, n-propyl, —CH2CH2CH3),2-propyl (i-Pr, i-propyl, —CH(CH3)2), 1-butyl (n-Bu, n-butyl,—CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, —CH2CH(CH3)2), 2-butyl(s-Bu, s-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH3)3), 1-pentyl (n-pentyl, —CH2CH2CH2CH2CH3), 2-pentyl(—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2-methyl-2-butyl(—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl(—CH2CH2CH(CH3)2), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), 1-hexyl(—CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2 CH3), 3-hexyl(—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3),3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2),2-methyl-3-pentyl (CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3,1-heptyl,1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp double bond, wherein thealkenyl radical includes radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations. Examples include, but arenot limited to, ethylenyl or vinyl (—CH═CH2), allyl (—CH2CH═CH2), andthe like. The term “alkynyl” refers to a linear or branched monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp triple bond. Examplesinclude, but are not limited to, ethynyl (—C≡CH), propynyl (propargyl,—CH2C≡CH), and the like.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF3, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. Cx aryl and Cx-Y aryl are typically used where X and Yindicate the number of carbon atoms in the ring.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl C(O)NH—.

The term “acylalkyl” is art-recognized and refers to an alkyl groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl C(O)alkyl.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds.

Moreover, such substituents include all those contemplated for alkylgroups, as discussed below, except where stability is prohibitive. Forexample, substitution of alkenyl groups by one or more alkyl,carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. Lower alkyls include methyl and ethyl. Incertain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxysubstituents defined herein are respectively lower acyl, lower acyloxy,lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether theyappear alone or in combination with other substituents, such as in therecitations hydroxyalkyl and aralkyl (in which case, for example, theatoms within the aryl group are not counted when counting the carbonatoms in the alkyl substituent).

The term “substituted” refers to moieties having substituents replacinghydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this application, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate.

Unless specifically stated as “unsubstituted,” references to chemicalmoieties herein are understood to include substituted variants. Forexample, reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (Ci-io) alkyl, alkylene, alkylidene, amide, amino,aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl,carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester,halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl,heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone,nitro, oxaalkyl and oxoalkyl moieties, each of which may optionally alsobe substituted or unsubstituted. In one particular embodiment, examplesof substituents include, but are not limited to, hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (Ci_io) alkoxy, (C4-12) aryloxy,hetero (Ci-io)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(Ci-10) alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10)alkyl, halo (Ci-10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10)alkyl, thiocarbonyl (Ci_i0) alkyl, sulfonyl (Ci-10) alkyl, sulfinyl(Ci_io) alkyl, (Ci_i0) azaalkyl, imino (Ci-10) alkyl, (C3-12) cycloalkyl(C1-5) alkyl, hetero (C3-12) cycloalkyl (Ci-I0) alkyl, aryl (Ci-I0)alkyl, hetero (Ci-10) aryl (C1-5) alkyl, (C9-12) bicycloaryl (Ci_s)alkyl, hetero (Ce-I2) bicycloaryl (Ci_(—)5) alkyl, (C3-12) cycloalkyl,hetero (C3-12) cycloalkyl, (C9-12) bicycloalkyl, hetero (C3-I2)bicycloalkyl, (C4-I2) aryl, hetero (Ci-10) aryl, (C9-12) bicycloaryl andhetero (C4-12) bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (Ci-10) alkoxy, (C4-I2) aryloxy, hetero (Ci-10) aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10) alkyl, halo (Ci-10)alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10) alkyl, thiocarbonyl(Ci-10) alkyl, sulfonyl (Ci-10) alkyl, sulfinyl (Ci-10) alkyl, (Ci-10)azaalkyl, imino (Ci_io) alkyl, (C3-I2) cycloalkyl (Ci-5) alkyl, hetero(C3-12) cycloalkyl (Ci-10) alkyl, aryl (Ci_io) alkyl, hetero (Ci-io)aryl (Ci_(—)5) alkyl, (C9-I2) bicycloaryl (C1-5) alkyl, hetero (C8-12)bicycloaryl (Ci_s) alkyl, (C3-12) cycloalkyl, hetero (C3_(—)12)cycloalkyl, (C9-12) bicycloalkyl, hetero (C3-12) bicycloalkyl, (C4-12)aryl, hetero (Ci-10) aryl, (C9-12) bicycloaryl and hetero (C4-12)bicycloaryl.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable salts. The compounds of the presentinvention can also be present in the form of pharmaceutically acceptableesters (i.e., the methyl and ethyl esters of the acids of formula 1 tobe used as prodrugs). The compounds of the present invention can also besolvated, i.e. hydrated. The solvation can be affected in the course ofthe manufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula 1(hydration).

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent. Metabolic condition associated diseasesinclude: Hepatic, Neurologic, Psychiatric, Hematologic, Renal,Cardiovascular, Cancer, Musculoskeletal, Orthopedic andGastrointestinal.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

“Residue” is an art-recognized term that refers to a portion of amolecule. For instance, a residue of thioctic acid may be: dihydrolipoicacid, bisnorlipoic acid, tetranorlipoic acid,6,8-bismethylmercapto-octanoic acid, 4,6-bismethylmercapto-hexanoicacid, 2,4-bismethylmeracapto-butanoic acid,4,6-bismethylmercapto-hexanoic acid.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityaccording to which a metabolic condition or neurodegenerative relateddiseases patient will suffer from abnormalities or complication and/orterminal renal failure and/or death (i.e. mortality) within a definedtime window (predictive window) in the future. The mortality may becaused by the central nervous system or complication. The predictivewindow is an interval in which the subject will develop one or more ofthe said complications according to the predicted probability. Thepredictive window may be the entire remaining lifespan of the subjectupon analysis by the method of the present invention. Preferably,however, the predictive window is an interval of one month, six monthsor one, two, three, four, five or ten years after appearance of thecardiovascular complication (more preferably and precisely, after thesample to be analyzed by the method of the present invention has beenobtained). As will be understood by those skilled in the art, such anassessment is usually not intended to be correct for 100% of thesubjects to be analyzed. The term, however, requires that the assessmentwill be valid for a statistically significant portion of the subjects tobe analyzed. Whether a portion is statistically significant can bedetermined without further ado by the person skilled in the art usingvarious well known statistic evaluation tools, e.g., determination ofconfidence intervals, p-value determination, Student's t-test,Mann-Whitney test, etc. Details are found in Dowdy and Wearden,Statistics for Research, John Wiley & Sons, New York 1983. Preferredconfidence intervals are at least 90%, at least 95%, at least 97%, atleast 98% or at least 99%. The p-values are, preferably, 0.1, 0.05,0.01, 0.005, or 0.0001. Preferably, the probability envisaged by thepresent invention allows that the prediction will be correct for atleast 60%, at least 70%, at least 80%, or at least 90% of the subjectsof a given cohort.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating the metabolic condition or neurodegenerative diseasecondition of a subject by administration of an agent even though suchagent does not treat the cause of the condition. The term “treating”,“treat” or “treatment” as used herein includes curative, preventative(e.g., prophylactic), adjunct and palliative treatment.

Metabolic condition related diseases or disorders includes such asaspartylglusomarinuria, biotimidase deficiency, carbohydrate deficientglycoprotein syndrome (CDGS), Crigler-Najjar syndrome, cystinosis,diabetes insipidus, Fabry, fatty acid metabolism disorders,galactosemia, Gaucher, glucose-6-phosphate dehydrogenase (G6PD),glutaric aciduria, Hurler, Hurler-Scheie, Hunter, hypophosphatemia,I-cell, Krabbe, lactic acidosis, long chain 3 hydroxyacyl CoAdehydrogenase deficiency (LCHAD), lysosomal storage diseases,mannosidosis, maple syrup urine, Maroteaux-Lamy, metachromaticleukodystrophy, mitochondrial, Morquio, mucopolysaccharidosis,neuro-metabolic, Niemann-Pick, organic acidemias, purine,phenylketonuria (PKU), Pompe, porphyria, pseudo-Hurler, pyruvatedehydrogenase deficiency, Sandhoff, Sanfilippo, Scheie, Sly, Tay-Sachs,trimethylaminuria (Fish-Malodor syndrome), urea cycle conditions, NASH,or any other medical condition, is well understood in the art, andincludes administration of a composition which reduces the frequency of,or delays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition.Neurodegenerative related diseases or disorders includes such asAlzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease, Spinalmuscular atrophy or any other medical condition, is well understood inthe art, and includes administration of a composition which reduces thefrequency of, or delays the onset of, symptoms of a medical condition ina subject relative to a subject which does not receive the composition.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the salts and compositions from the subject compositions. It isto be noted that dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. Typically, dosing will be determined using techniquesknown to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular salt or composition may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

The term “solvate” as used herein, refers to a compound formed bysolvation (e.g., a compound formed by the combination of solventmolecules with molecules or ions of the solute).

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive salt and/or composition, for a sustained or extended period (ascompared to the release from a bolus). This release may result inprolonged delivery of therapeutically effective amounts of any of thetherapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable salts of saidprodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof Formula 1 may be formulated for systemic or topical or oraladministration. The pharmaceutical composition may be also formulatedfor oral administration, oral solution, injection, subdermaladministration, or transdermal administration. The pharmaceuticalcomposition may further comprise at least one of a pharmaceuticallyacceptable stabilizer, diluent, surfactant, filler, binder, andlubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (Formulas I)to be delivered in an amount sufficient to deliver to a patient atherapeutically effective amount of a compound of formula 1 orcomposition as part of a prophylactic or therapeutic treatment. Thedesired concentration of formula for its pharmaceutical acceptable saltswill depend on absorption, inactivation, and excretion rates of the drugas well as the delivery rate of the salts and compositions from thesubject compositions. It is to be noted that dosage values may also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula 1 may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

The concentration and/or amount of any compound of formula 1 may bereadily identified by routine screening in animals, e.g., rats, byscreening a range of concentration and/or amounts of the material inquestion using appropriate assays. Known methods are also available toassay local tissue concentrations, diffusion rates of the salts orcompositions, and local blood flow before and after administration oftherapeutic formulations disclosed herein. One such method ismicrodialysis, as reviewed by T. E. Robinson et al., 1991, microdialysisin the neurosciences, Techniques, volume 7, Chapter 1. The methodsreviewed by Robinson may be applied, in brief, as follows. Amicrodialysis loop is placed in situ in a test animal. Dialysis fluid ispumped through the loop. When compounds with formula 1 such as thosedisclosed herein are injected adjacent to the loop, released drugs arecollected in the dialysate in proportion to their local tissueconcentrations. The progress of diffusion of the salts or compositionsmay be determined thereby with suitable calibration procedures usingknown concentrations of salts or compositions.

In certain embodiments, the dosage of the subject compounds of formula 1provided herein may be determined by reference to the plasmaconcentrations of the therapeutic composition or other encapsulatedmaterials. For example, the maximum plasma concentration (Cmax) and thearea under the plasma concentration-time curve from time 0 to infinitymay be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of Formulas I is in the range ofabout 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses,for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divideddoses. The compounds of Formulas I may be administered at a dose of, forexample, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.Compounds of Formula 1 may also be administered to a human patient at adose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500,800, 1000 mg per day. In certain embodiments, the compositions hereinare administered at an amount that is less than 95%, 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, or 10% of the compound of formula 1 required for thesame therapeutic benefit.

An effective amount of the compounds of formula 1 described hereinrefers to the amount of one of said salts or compositions which iscapable of inhibiting or preventing a disease. For example Metaboliccondition associated disease symptoms such as inborn errors ofmetabolism includes cystinosis, NASH, diabetes and renal andNeurodegenerative diseases include disease symptoms associated toAlzheimer's, Huntingtons disease, Parkinsons disease and lateralsclerosis. An effective amount may be sufficient to prohibit, treat,alleviate, ameliorate, halt, restrain, slow or reverse the progression,or reduce the severity of a complication resulting from nerve damage ordemyelization and/or elevated reactive oxidative-nitrosative speciesand/or abnormalities in neurotransmitter homeostasis's, in patients whoare at risk for such complications. As such, these methods include bothmedical therapeutic (acute) and/or prophylactic (prevention)administration as appropriate. The amount and timing of compositionsadministered will, of course, be dependent on the subject being treated,on the severity of the affliction, on the manner of administration andon the judgment of the prescribing physician. Thus, because ofpatient-to-patient variability, the dosages given above are a guidelineand the physician may titrate doses of the drug to achieve the treatmentthat the physician considers appropriate for the patient. In consideringthe degree of treatment desired, the physician must balance a variety offactors such as age of the patient, presence of preexisting disease, aswell as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula 1 may also comprise enterically coated comprisingof various excipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula 1 disclosed herein, for instance,compounds of formula 1 or pharmaceutical acceptable salts of a compoundsof Formula 1.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of theneoplastic disease; the type of host involved, including its age, healthand weight; the kind of concurrent treatment, if any; the frequency oftreatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

Powders are prepared quite simply by comminuting the active ingredientto a suitably fine size and mixing with a similarly comminuted diluent.The diluent can be an edible carbohydrate material such as lactose orstarch. Advantageously, a sweetening agent or sugar is present as wellas flavoring oil.

Capsules are produced by preparing a powder mixture as hereinbeforedescribed and filling into formed gelatin sheaths. Advantageously, as anadjuvant to the filling operation, a lubricant such as talc, magnesiumstearate, calcium stearate and the like is added to the powder mixturebefore the filling operation.

Soft gelatin capsules are prepared by machine encapsulation of slurry ofactive ingredients with an acceptable vegetable oil, light liquidpetrolatum or other inert oil or triglyceride.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing an active ingredient, suitably comminuted, with adiluent or base such as starch, lactose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as corn syrup, gelatin solution, methylcellulose solution or acaciamucilage and forcing through a screen. As an alternative to granulating,the powder mixture can be slugged, i.e., ran through the tablet machineand the resulting imperfectly formed tablets broken into pieces (slugs).The slugs can be lubricated to prevent sticking to the tablet-formingdies by means of the addition of stearic acid, a stearic salt, talc ormineral oil. The lubricated mixture is then compressed into tablets.

Advantageously, the tablet can be provided with a protective coatingconsisting of a sealing coat or enteric coat of shellac, a coating ofsugar and methylcellulose and polish coating of carnauba wax.

Fluid unit dosage forms for oral administration such as in syrups,elixirs and suspensions can be prepared wherein each teaspoonful ofcomposition contains a predetermined amount of an active ingredient foradministration. The water-soluble forms can be dissolved in an aqueousvehicle together with sugar, flavoring agents and preservatives to forma syrup. An elixir is prepared by using a hydroalcoholic vehicle withsuitable sweeteners together with a flavoring agent. Suspensions can beprepared of the insoluble forms with a suitable vehicle with the aid ofa suspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing an active ingredient and a sterile vehicle, water beingpreferred. The active ingredient, depending on the form andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the water-soluble active ingredient can bedissolved in water for injection and filter sterilized before fillinginto a suitable vial or ampule and sealing. Advantageously, adjuvantssuch as a local anesthetic, preservative and buffering agents can bedissolved in the vehicle. Parenteral suspensions are prepared insubstantially the same manner except that an active, ingredient issuspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The active ingredient can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of theactive ingredient.

In addition to oral and parenteral administration, the rectal andvaginal routes can be utilized. An active ingredient can be administeredby means of a suppository. A vehicle which has a melting point at aboutbody temperature or one that is readily soluble can be utilized. Forexample, cocoa butter and various polyethylene glycols (Carbowaxes) canserve as the vehicle.

For intranasal instillation, a fluid unit dosage form is preparedutilizing an active ingredient and a suitable pharmaceutical vehicle,preferably P.F. water, a dry powder can be formulated when insufflationis the administration of choice.

For use as aerosols, the active ingredients can be packaged in apressurized aerosol container together with a gaseous or liquifiedpropellant, for example, dichlorodifluoromethane, carbon dioxide,nitrogen, propane, and the like, with the usual adjuvants such ascosolvents and wetting agents, as may be necessary or desirable.

The term “unit dosage form” as used in the specification and claimsrefers to physically discrete units suitable as unitary dosages forhuman and animal subjects, each unit containing a predetermined quantityof active material calculated to produce the desired therapeutic effectin association with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and are directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitation inherent in the art ofcompounding such an active material for therapeutic use in humans, asdisclosed in this specification, these being features of the presentinvention. Examples of suitable unit dosage forms in accord with thisinvention are tablets, capsules, troches, suppositories, powder packets,wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules,vials, segregated multiples of any of the foregoing, and other forms asherein described.

The tablets of the present invention contain one or morepharmaceutically active agents that are released therefrom upon contactof the tablet with a liquid medium, for example a dissolution mediumsuch as gastrointestinal fluids. “Water soluble,” as used herein inconnection with non-polymeric materials, shall mean from sparinglysoluble to very soluble, i.e., not more than 100 parts water required todissolve 1 part of the non-polymeric, water soluble solute. SeeRemington, The Science and Practice of Pharmacy, pp 208-209 (2000).“Water soluble,” as used herein in connection with polymeric materials,shall mean that the polymer swells in water and can be dispersed at themolecular level or dissolved in water.

As used herein, the term “modified release” shall apply to tablets,matrices, particles, coatings, portions thereof, or compositions thatalter the release of an pharmaceutically active agent in any manner.Types of modified release include controlled, prolonged, sustained,extended, delayed, pulsatile, repeat action, and the like. Suitablemechanisms for achieving these types of modified release includediffusion, erosion, surface area control via geometry and/or impermeablebarriers, or other mechanisms known in the art.

In one embodiment of the invention, the first pharmaceutically activeagent and the hydrophilic polymer are mixed with a powder containing apharmaceutically-acceptable carrier, which is also defined herein as thetablet matrix. In one embodiment, the powder has an average particlesize of about 50 microns to about 500 microns, such as between 50microns and 300 microns. Particles in this size range are particularlyuseful for direct compression processes. In embodiment, the componentsof powder are blended together, for example as dry powders, and fed intothe die cavity of an apparatus that applies pressure to form a tabletcore. Any suitable compacting apparatus may be used, including, but notlimited to, conventional unitary or rotary tablet press. In oneembodiment, the tablet core may be formed by compaction using a rotarytablet press (e.g., such as those commercially available from FetteAmerica Inc., Rockaway, N.J., or Manesty Machines LTD, Liverpool, UK).In general, a metered volume of powder is filled into a die cavity(where the powder is either gravity fed or mechanically fed from afeeder) of the rotary tablet press, and the cavity rotates as part of a“die table” from the filling position to a compaction position. At thecompaction position, the powder is compacted between an upper and alower punch, then the resulting tablet core is pushed from the diecavity by the lower punch and then guided to an injection chute by astationary “take-off bar.

In one embodiment of the invention, the tablet core may be a directlycompressed tablet core made from a powder that is substantially free ofwater-soluble polymeric binders and hydrated polymers. As used herein,what is meant by “substantially free” is less than 5 percent, such asless than 1 percent, such as less than 0.1 percent, such as completelyfree (e.g., 0 percent). This composition is advantageous for minimizingprocessing and material costs and providing for optimal physical andchemical stability of the tablet core. In one embodiment, the density ofthe tablet core is greater than about 0.9 g/cc.

The tablet core may have one of a variety of different shapes. Forexample, the tablet core may be shaped as a polyhedron, such as a cube,pyramid, prism, or the like; or may have the geometry of a space figurewith some non-flat faces, such as a cone, truncated cone, cylinder,sphere, torus, or the like. In certain embodiments, a tablet core hasone or more major faces. For example, the tablet core surface typicallyhas opposing upper and lower faces formed by contact with the upper andlower punch faces in the compression machine. In such embodiments thetablet core surface typically further includes a “belly-band” locatedbetween the upper and lower faces, and formed by contact with the diewalls in the compression machine.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

In one embodiment, an osmogen is incorporated into the tablet core inorder to draw water into the tablet upon contact with fluids, such asgastrointestinal fluids. An osmogen as used herein is a water solublecomponent which preferentially draws water into the tablet core for thepurposes of distributing the water throughout the core, so that theactive ingredient contained in the core may be released. In oneembodiment the osmogen is a salt such as but not limited to sodiumchloride, potassium chloride, sodium citrate, or potassium citrate.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable fillers include, but are not limited to, watersolublecompressible carbohydrates such as sugars (e.g., dextrose, sucrose,maltose, and lactose), starches (e.g., corn starch), sugar-alcohols(e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starchhydrolysates (e.g., dextrins, and maltodextrins), and water insolubleplastically deforming materials (e.g., microcrystalline cellulose orother cellulosic derivatives), and mixtures thereof. Suitable adsorbents(e.g., to adsorb the liquid drug composition) include, but are notlimited to, water-insoluble adsorbents such as dicalcium phosphate,tricalcium phosphate, silicified microcrystalline cellulose (e.g., suchas distributed under the PROSOLV brand (PenWest Pharmaceuticals,Patterson, N.Y.)), magnesium aluminometasilicate (e.g., such asdistributed under the NEUSILIN™ brand (Fuji Chemical Industries (USA)Inc., Robbinsville, N.J.), clays, silicas, bentonite, zeolites,magnesium silicates, hydrotalcite, veegum, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof. Suitable glidants include,but are not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirsalts, and mixtures thereof. Examples of suitable fatty acid estersinclude, but are not limited to, sucrose fatty acid esters, mono-, di-,and triglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoylmacrogol-32 glycerides, and mixtures thereof. Examples of suitablephospholipids include phosphotidyl choline, phosphotidyl serene,phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examplesof suitable waxes include, but are not limited to, carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate, andmixtures thereof. Examples of super disintegrants include, but are notlimited to, croscarmellose sodium, sodium starch glycolate andcross-linked povidone (crospovidone). In one embodiment the tablet corecontains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

In some cases, it may be desirable to administer in the form of a kit,it may comprise a container for containing the separate compositionssuch as a divided bottle or a divided foil packet. Typically the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a plastic material that may betransparent. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. In some embodiments the strength of the sheet is such that thetablets or capsules can be removed from the blister pack by manuallyapplying pressure on the recesses whereby an opening is formed in thesheet at the place of the recess. The tablet or capsule can then beremoved via said opening.

Method of Synthesis:

Synthesis of Compound of Formula 1:

STEP-1: Reaction of 2-Bromoethylamine Hydrobromide with Potassiumthioacetate to Obtain Compound 2:

Procedure:

To the solution of 2-Bromoethylamine Hydrobromide (100.0 g, 488 mmol;1.0 eq) in Dimethylformamide (0.6 L), Potassium thioacetate (55.73 g,488 mmol; 1 eq) was added at room temperature. The reaction mixture wasleft stirring for 24 hr at room temperature. On completion of thereaction (monitored by TLC), the solvent was distilled from the reactionmixture completely and Co-distilled with acetonitrile. Acetonitrile wasadded (1 L) to the reaction mass and warmed up to 85° C. and maintainedat 85° C. for 1 hr. The reaction mass was cooled slowly to 0° C. and awhite solid was obtained. The white Solid was filtered and washed withacetonitrile (500 mL) to yield 40.0 g (68.9%, based on Potassiumthioacetate) of compound 2 as a white solid.

TABLE 1 ¹H NMR (DMSO-d₆, 300 MHz) splitting pattern & J δ value ProtonsGroup 8.01-7.99 s 1H NH₂ 3.12-3.05 m 2H CH₂ 3.02-2.90 s 2H CH₂ 2.38-2.41s 3H CH₃

Step 2 for Formula 1 Amide: Reaction of Compound-2 with ChloroacetylChloride to Provide Compound 3.

Procedure:

To a 1 L round bottom flask, compound 2 (8 g, 67.1 mmol; 1.0 eq),hydroxybenzotriazole (HOBT, 9 g, 67.1 mmol; 1.0 eq) and Eicosapentaenoicacid (EPA, 20.30 g, 67.1 mmol; 1.0 eq) were mixed with Dimethylformamide(DMF, 200 mL, 25 V, GR grade were added at room temperature, then1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDCI.HCl, 19.30 g, 100.0mmol; 1.50 eq) added to it, the reaction mixture was allowed to stir for4-5 h at RT. Reaction was monitored by TLC. On completion of thereaction, the reaction mixture was diluted with Diethyl ether (2.0 L),washed with water (2×1.0 L) followed by brine solution (1.0 L) and driedover anhydrous Na₂SO₄ and evaporated under reduced pressure. The crudewas purified by column chromatography over 100-200 mesh silica gel byusing 10-15% ethyl acetate-hexane to yield 5.0 g (18.5%) of compound 3as a pale yellow gum.

TABLE 2 ¹H NMR (CDCl₃, 300 MHz) δ: splitting pattern & J δ value ProtonsGroup 5.75 s 1H NH 5.42-5.32 m 10H  CH═CH 3.44-3-43 m 2H CH₂ 3.10-3.07 m2H CH₂ 2.84-2.76 m 8H 4CH₂ 2.45-2.41 s 3H CH₃ 2.18-2.04 m 6H 3CH₂ 1.58 m2H CH₂ 0.99-0.95 t = 7.6 Hz 3H CH₃

Carbon Skeletal formula: Molecular formula: C₂₄H₃₇NO₂S, Molecularweight: 404.

TABLE 3 ¹³C NMR(CDCl₃, 300 MHz) δ: Carbon δ position Group 195.90 C23SCO 172.95 C20 NHCO 131.83 C16 CH 128.92 C15 CH 128.55 C13 CH 128.39 C12CH 128.08 C10 CH 128.04 C9 CH 127.97 C7 CH 127.90 C6 CH 127.68 C4 CH126.83 C3 CH 39.23 C21 CH₂ 35.75 C22 2CH2 30.40 C19 CH₂ 29.48 C17 2CH₂28.65 C24 CH₃ 26.49 C18 CH₂ 25.46 C14 CH₂ 25.36 C11, C8 2CH₂ 25.30 C5CH₂ 20.37 C2 CH₂ 14.08 C1 CH3

Method of Pharmacokinetic Parameter Estimation

Parameter estimation was performed on mean plasma and brainEicosapentanoiec acid, KB-ND-002 and Cysteamine concentration vs nominalsampling time values from 3 animals per timepoint. Parameter estimateswere derived for each analyte, and matrix using a non-compartmentalapproach in WinNonlin Enterprise version 5.2.1 (Pharsight Corp.,Mountain View, Calif., USA) in accordance with Charles River standardoperating procedures. A WinNonlin regression analysis was performed witheach concentration vs time profile reviewed by means of visualinspection to appropriately characterise the apparent terminalelimination phase and optimise the reliability of the lambda-zestimation.

Parameter Definitions

Parameter Definition of parameter Cmax The maximum observed meanEicosapentanoiec acid, KB-ND-002 and Cysteamine concentration afterdosing. Cmax/D The Cmax divided by the dose administered. Tmax The timeafter dosing at which the maximum Eicosapentanoiec acid, KB-ND-002 andCysteamine concentration was observed. AUC(0-t) The area under the meanEicosapentanoiec acid, KB-ND-002 and Cysteamine concentration vs timecurve from time zero to the time after dosing at which the lastquantifiable concentration of the drug was observed (Tlast) estimated bythe linear trapezoidal method. AUC(0-t)/D The AUC(0-t) divided by thedose administered. AUC(0-inf) The area under the Eicosapentanoiec acid,KB-ND-002 and Cysteamine concentration vs time curve from time zero toinfinity: AUC(0-inf) = AUC(0-t) + (Clast/Kel) where Clast = theconcentration at time Tlast and Kel = apparent terminal elimination rateconstant. AUC(0-inf)/D The AUC(0-inf) divided by the dose administered.T½ The apparent terminal elimination half life: T½ = ln 2/Kel; where Kel= apparent terminal elimination rate constant. Rsq The square of thecorrelation coefficient for the terminal elimination phase regressionline.

Following oral administration of KB-ND-002 (Formula 1), Cysteamine orEicosapentanoiec acid in male mice, concentration vs time profiles werepartially evaluable for PK purposes.

Eicosapentanoiec Acid

There were no parameter estimates generated for control group animals,however the endogenous Eicosapentanoiec acid concentration data inplasma and brain were reviewed. Concentrations of Eicosapentanoiec acidin control animals were between 5 and 15-fold higher in brain than inplasma. For Groups 1 to 4, maximum concentrations of Eicosapentanoiecacid after dosing increased by approximately 3-fold when compared toendogenous levels in the control group animals in plasma. In brain, Cmaxestimates for Groups 1 to 4 were generally comparable to controlanimals. In Group 5 however, the difference between endogenousEicosapentanoiec acid and administered Eicosapentanoiec acid was over20-fold in plasma. Concentrations of Eicosapentanoiec acid in plasma andbrain were quantifiable for the entire duration of sampling of 5 h(Graphs 1 to 4). In Group 5, peak concentrations of Eicosapentanoiecacid were observed 1 h following dosing of 112 mg/kg Eicosapentanoiecacid in both plasma and brain. Systemic exposure to Eicosapentanoiecacid was greatest when 112 mg/kg Eicosapentanoiec acid was administered.Systemic exposure to Eicosapentanoiec acid decreased with increasingdoses of KB-ND-002.

KB-ND-002 (Formula I)

Following dosing of KB-ND-002, systemic exposure to KB-ND-002 in plasma(as indicated by Cmax and AUC(0-t) estimates) increased with increasingdose. Based on the dose normalised estimates of Cmax and AUC(0-t), thisincrease was sub-proportional possibly indicating limitations in theabsorption of KB-ND-002 at high doses.In brain, quantifiable concentrations of KB-ND-002 were only evidentfollowing the highest dose of KB-ND-002. Systemic exposure to KB-ND-002observed at this dose level in brain was <1% of that observed in plasmafollowing administration of the low dose of KB-ND-002 (60 mg/kg).

Cysteamine

There were no parameter estimates generated for control group animals,however the endogenous Cysteamine concentration data in plasma and brainwere reviewed. Concentrations of Cysteamine in control animals werereadily quantifiable in brain than in plasma; between 7 and 12-foldhigher in brain than in plasma. For Groups 1, 2, 3 and 5, maximumconcentrations of Cysteamine after dosing increased by up toapproximately 3-fold when compared to endogenous levels in the controlgroup animals both in plasma and brain. In Group 4 however, thedifference between endogenous Cysteamine and administered Cysteamine wasover 400-fold in plasma. In brain, the difference between endogenousCysteamine and administered Cysteamine was up to 10-fold. Concentrationsof Cysteamine in brain were quantifiable for the entire duration ofsampling of 5 h. However, in plasma, concentrations of Cysteamine wereonly consistently observed for the entire duration of sampling followingadministration of Cysteamine (Group 4). In Group 4, peak concentrationsof Cysteamine were observed 0.08 h and 0.5 h following dosing of 112mg/kg Cysteamine in both plasma and brain, respectively. Systemicexposure to Cysteamine was greatest when 112 mg/kg Cysteamine wasadministered. No further meaningful interpretation of parameterestimates were possible due to Cysteamine being an endogenous substance.Concentrations of Eicosapentanoiec acid in brain were between 1.2 to2.7-fold higher than Cysteamine.

The present disclosure provides among other things compositions andmethods for treating metabolic conditions, cystinosis, non-alcoholicSteatohepatitis, hypertriglyceridemia or neurodegenerative disorders andtheir complications. While specific embodiments of the subjectdisclosure have been discussed, the above specification is illustrativeand not restrictive. Many variations of the compounds and methods hereinwill become apparent to those skilled in the art upon review of thisspecification. The full scope of the claimed compounds and methodsshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

What is claimed is:
 1. A method of treating at least one of acardiovascular disease, a hepatic disease, a genetic disorder, and ametabolic disorder comprising: administering the compound of Formula 1to a patient suffering from at least one of a cardiovascular disease, ahepatic disease, a genetic disorder, and a metabolic disorder.


2. The method of claim 1, further comprising administering the compoundof comprising Formula 1 through at least one of a non-invasive peroral,a topical ointment, an enteral, a gel solution, a syrup, a lotion, ahealing pad, a transmucosal delivery, a targeted delivery, a sustainedrelease delivery, a delayed release delivery, a pulsed release delivery,a patch, and a parenteral delivery.
 3. The method of claim 2, whereinthe method treats at least one of a hypertriglyceridemia disorder, astroke, an atrial fibrillation, a coronary heart disease, anon-alcoholic Steatohepatitis, cystinosis, nephropathic cystinosis, andHuntington's disease.